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Inflammation in Chronic Heart Failure (June).
Ann Pharmacother. 2008 May 13;
Parish RC, Evans JD
OBJECTIVE: To summarize findings regarding the association of inflammatory processes with chronic heart failure (HF). DATA SOURCES: We conducted PubMed/MEDLINE searches (1966-January 2008) of primary literature using the following key words: ACE inhibitors, allopurinol, angiotensin-receptor antagonists, cardiomyopathy, chemokines, cytokines, diuretics, heart failure, inflammation, interleukins, HMG-CoA reductase inhibitors, immunotherapy, medications used in heart failure, thalidomide, tumor necrosis factor, and uric acid. STUDY SELECTION AND DATA EXTRACTION: All articles that appeared to be relevant were read; of 305 articles examined, 87 were selected for discussion. Articles were selected if they were written in English and focused on any of the key words or appeared to have substantial content addressing inflammation in HF. DATA SYNTHESIS: Cytokines, uric acid, and other inflammatory mediators are associated with physiologic effects that are also prominent features of HF (eg, reduced contractility and cardiac output, endothelial dysfunction, hypercoagulability, autonomic dysfunction as evidenced by reduced resting heart rate variability, insulin resistance). With the exception of elevated tumor necrosis factor-alpha as a cause of insulin resistance, it is not clear whether elevated inflammatory mediators directly cause HF signs and symptoms or whether they are incidental markers. Awareness of these associations has occurred relatively recently; there have been few clinical studies of efforts to directly modify inflammatory mediators. Most currently accepted drug therapies of HF reduce concentrations of circulating cytokines, but the significance of these findings awaits directed study. CONCLUSIONS: Loss of myocardial function, autonomic dysfunction, and glucose intolerance are interrelated and linked by underlying chronic low-grade inflammation. Drug therapy with statins, pentoxifylline, and perhaps urate-lowering agents, in addition to current therapies, holds promise for treatment of HF.
Protective effects of apocynin and allopurinol on ischemia/reperfusion-induced liver injury in mice.
World J Gastroenterol. 2008 May 14; 14(18): 2832-7
Liu PG, He SQ, Zhang YH, Wu J
AIM: To determine the effects of allopurinol, an inhibitor of xanthine oxidase, and apocynin, an inhibitor of NADPH oxidase, on oxidant stress and liver injury caused by hepatic ischemia/reperfusion (I/R) procedure in mice. METHODS: Mice were pretreated with a xanthine oxidase inhibitor, allopurinol, or NADPH oxidase (NOX) inhibitor, apocynin before the hepatic I/R procedure. Then treated or untreated mice underwent the hepatic I/R procedure. The effects on hepatic injury and superoxide anions were determined after starting reperfusion. RESULTS: A standard warm hepatic I/R procedure led to a marked increase in superoxide anion production as indicated by a superoxide anion tracer, MCLA. At the same time, the procedure caused profound acute liver injury, as indicated by elevated serum alanine aminotransferase and tumor necrosis factor-alpha levels, reduced liver glutathione levels and elevated malondialdehyde contents, as well as a high apoptotic cell count. All these changes were reversed by the use of apocynin or allopurinol prior to the hepatic I/R procedure. CONCLUSION: Allopurinol and apocynin exerted protective effects on hepatic ischemia/reperfusion injury. The protection is associated with blocking the generation of superoxide anions during the hepatic I/R procedure by inhibiting xanthine oxidase and NADPH oxidase activity.
The role of urate and xanthine oxidase inhibitors in cardiovascular disease.
Cardiovasc Ther. 2008; 26(1): 59-64
George J, Struthers AD
Many studies have shown a strong correlation between urate levels and cardiovascular disease. The formation of urate is complex as the same enzyme that produces urate, xanthine oxidase (XO) also catalyzes the formation of reactive oxygen species (ROS). There is some evidence that the urate molecule has free radical scavenging properties in vitro and acute infusions of urate improve endothelial function in at-risk populations. High levels of ROS are clearly linked to worse outcome in a variety of conditions. Allopurinol has been the archetypal XO inhibitor for over 40 years. Small studies have demonstrated its beneficial effects, mainly in heart failure but also in a variety of other cohorts of patients with cardiovascular risk. It is a safe agent, provided suitable patients are chosen and monitored carefully. Newer promising agents like oxypurinol have not shown the expected benefits in larger multicentered studies. This review looks at the biology of urate, its role in cardiovascular disease, the possible mechanisms by which XO inhibitors exert their beneficial effect on endothelial dysfunction, and examines the possible causes for the failure of newer agents to live up to expectations.
Allopurinol hypersensitivity syndrome: a preventable severe cutaneous adverse reaction?
Singapore Med J. 2008 May; 49(5): 384-7
Lee HY, Ariyasinghe JT, Thirumoorthy T
INTRODUCTION: Allopurinol is a widely-prescribed urate-lowering agent. Allopurinol hypersensitivity syndrome, a severe form of cutaneous adverse reaction, is associated with significant mortality and morbidity. The aim of this study was to document the clinical presentation of allopurinol hypersensitivity in a local population, examine the indications for urate-lowering therapy and to identify potential associations with such a syndrome. METHODS: Retrospective review was done for all patients who were referred to the dermatology unit of a tertiary hospital for allopurinol hypersensitivity syndrome over a four-year period. RESULTS: Over four years, there were 28 patients with allopurinol hypersensitivity syndrome, of which there were 27 (96 percent) Chinese and one (four percent) Malay. The average age was 69 years. At baseline, 24 patients (86 percent) had renal impairment, and 21 patients (75 percent) had higher dosages of allopurinol. The cutaneous manifestation included generalised maculopapular exanthem (22 patients, 79 percent), Stevens Johnson/toxic epidermal necrolysis overlap (two patients, seven percent) and Stevens-Johnson syndrome (two patients, seven percent) and generalised exfoliative dermatitis (one patient, four percent). Mortality rate was 18 percent. Indications for allopurinol therapy were clear in ten patients (36 percent). CONCLUSION: Allopurinol hypersensitivit y syndrome is a life-threatening cutaneous adverse reaction. Allopurinol should be initiated under clear indications with appropriate dosages. Potential associations with this syndrome include the Chinese race, the elderly, and patients with underlying renal impairment.
Ann Dermatol Venereol. 2008 May; 135(5): 393-396
Goldman J, Duval-Modeste AB, Lambert A, Contentin N, Courville P, Musette P, Joly P
BACKGROUND: Imatinib (Glivec((R))) is a tyrosine kinase inhibitor used to treat certain cases of leukaemia. We report a case of a drug-induced reaction with eosinophilia and systemic symptoms (DRESS) caused by imatinib. CASE-REPORT: A 77-year-old woman with a chronic myeloid leukaemia was treated with imatinib and allopurinol. Nineteen days after the start of treatment, the patient presented fever with a generalized polymorphous rash associated with oral erosions, facial oedema, diffuse lymphadenopathy and blood hypereosinophilia. Histological analysis of skin biopsy specimens suggested a drug-induced reaction. The outcome was favourable two weeks after discontinuation of treatment. Three months later, imatinib was reintroduced because of progression of the patient's chronic myeloid leukaemia, and recurrence of the skin rash and fever was observed within 12hours. DISCUSSION: Allopurinol was stopped definitively because of its more frequent imputability. Imatinib was reintroduced after considering the benefit-risk ratio and in full knowledge of the existence of cutaneous reactions to imatinib, despite there being only one recent report of DRESS following treatment with imatinib. According to the causality criteria of Bégaud et al. regarding imatinib, inherent causality of the drug in our patient was initially possible (I2) and appeared likely (I3) after the rechallenge test. This case clearly illustrates that imatinib is a potential cause of DRESS.
Gout and related morbid conditions: pharmacological and SPA therapy.
Minerva Med. 2008 Apr; 99(2): 203-12
Petraccia L, Fraioli A, Liberati G, Lopalco M, Grassi M
Gouty arthritis is estimated to be the most frequent manifestation of inflammatory arthritis in men aged over 40. Hyperuricemia occurs because of both exogenous and genetic factors, which are particularly influential in some populations such as Taiwan aborigines. Current understanding of the disease etiopathogenesis, its clinical manifestations and the stages of its progression are presented here. The criteria for a correct diagnosis of the disease are also reported, pointing out how to distinguish gout from clinical events of different origin but with a very similar symptomatology. A distinction is made between the agents used to relieve the acute attack (colchicine, nonsteroidal anti-inflammatory drugs, corticosteroids) and those used with the purpose of correcting hyperuricemia and preventing recurrences and complications (allopurinol, uricosurics). Mecha-nisms of action, administration routes, doses, side effects and contraindications of every drug are described. Besides pharmacological therapy, the importance and the efficacy of spa therapy is underlined. Finally, perspectives opened by gene therapy are mentioned.
J Clin Rheumatol. 2008 Feb; 14(1): 6-11
Panomvana D, Sripradit S, Angthararak S
BACKGROUND: Lower dosages of allopurinol are recommended to avoid toxicity in gout patients with impaired renal function. This often has resulted in inadequate control of hyperuricemia. The optimum therapeutic range of plasma oxypurinol concentrations in gout patients with chronic kidney disease has never been investigated. This study was performed to examine the relationships between plasma oxypurinol concentrations and the changes in serum urate level and renal function after taking a standard dose of allopurinol, 300 mg daily, in gout patients with renal insufficiency. PATIENTS AND METHODS: The study was conducted in 27 gout patients with renal insufficiency in a rheumatology clinic at the Rajvithi Hospital, Bangkok. Both new and current patients, after they discontinued allopurinol completely for 4 weeks, were treated with allopurinol 300 mg daily for 6 weeks. Blood samples were collected immediately before and 5 hours after the studied dose had been taken. Serum urate levels and renal function were recorded before and after the 6 weeks of allopurinol treatments. RESULTS: Most patients receiving allopurinol 300 mg/d had their plasma oxypurinol concentrations higher than the proposed therapeutic range for patients with normal renal function. There were significant relationships between changes in serum urate level with both trough and fifth-hour oxypurinol concentrations (R = 0.42, P = 0.002 and R = 0.27, P = 0.007, respectively). Higher plasma oxypurinol concentrations resulted in a higher percentage of patients who could meet the therapeutic treatment goal. No serious side effect and no significantly change in creatinine clearance were observed indicating that high levels of oxypurinol did not appear to relate to higher prevalence of adverse reaction. CONCLUSIONS: Higher percentages of patients could meet the treatment goal when their plasma oxypurinol concentrations were higher than the proposed therapeutic range for patients with normal renal function.
Cochrane Database Syst Rev. 2008; CD006817
Chaudhari T, McGuire W
BACKGROUND: Delayed neuronal death following a perinatal hypoxic insult is due partly to xanthine oxidase-mediated production of cytotoxic free radicals. Evidence exists that allopurinol, a xanthine-oxidase inhibitor, reduces delayed cell death in animal models of perinatal asphyxia and in human patients with other forms of organ reperfusion injury. OBJECTIVES: To determine the effect of allopurinol on mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2007), MEDLINE (1966 - December 2007), EMBASE (1980 - December 2007), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared allopurinol administration vs. placebo or no drug in newborn infants with suspected hypoxic-ischaemic encephalopathy. DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Neonatal Review Group were used, with separate evaluation of trial quality and data extraction by two authors. Data were synthesised using a fixed effects model and reported using typical relative risk, typical risk difference and weighted mean difference. MAIN RESULTS: Three trials in which a total of 114 infants participated were identified. In one trial, participants were exclusively infants with severe encephalopathy. The other trials also included infants with mild and moderately-severe encephalopathy. These studies were generally of good methodological quality, but were underpowered to detect clinically important effects of allopurinol on mortality and morbidity. Meta-analysis did not reveal a statistically significant difference in the risk of death during infancy [typical relative risk 0.92 (95% confidence interval 0.59 to 1.45); typical risk difference -0.03 (95% confidence interval -0.16 to 0.11)], nor in the incidence of neonatal seizures [typical relative risk 0.93 (95% confidence interval 0.75 to 1.16); typical risk difference -0.05 (95% confidence interval -0.21 to 0.11)]. Only one trial assessed neurodevelopment in surviving children and did not find a statistically significant effect. AUTHORS' CONCLUSIONS: The available data are not sufficient to determine whether allopurinol has clinically important benefits for newborn infants with hypoxic-ischaemic encephalopathy and, therefore, larger trials are needed. Such trials could assess allopurinol as an adjunct to therapeutic hypothermia in infants with moderate and severe encephalopathy and should be designed to exclude clinically important effects on mortality and adverse long-term neurodevelopmental outcomes.
Utilization of allopurinol in the Australian community.
Intern Med J. 2008 Apr 14;
Chung Y, Lu CY, Graham GG, Mant A, Day RO
Background: International data suggest that suboptimal use of allopurinol is common. Allopurinol dose should be lower in renal impairment, but higher when gout is not controlled. The aim of the study was to examine trends in the usage of allopurinol in the Australian community. Methods: Community dispensing data on the urate-lowering drugs allopurinol and probenecid were obtained from databases kept by Medicare Australia and the Drug Utilization Sub-Committee, for January 1992 to December 2005. Results: Allopurinol comprised 98.4% of all prescriptions for urate-lowering drugs dispensed during 2005. Most prescriptions were for allopurinol 300 mg, but there was a steady shift towards use of allopurinol 100 mg in all states and territories over the period of the study. There were marked variations in prescribing rates across the country. New South Wales had the highest rate of subsidized prescribing for allopurinol 300 mg (39.3 per 1000 population). Tasmania had the highest rate for allopurinol 100 mg (14.3 per 1000 population), which coincided with an educational programme to decrease allopurinol dose in patients with renal impairment. Prescribing rates in the Northern Territory were substantially lower than all other regions, at 10.8 and 3.3 prescriptions per 1000 population for allopurinol 300 and 100 mg, respectively. Conclusion: The increased uptake of allopurinol 100 mg suggests greater adherence to dosing guidelines and that there is value in educational programmes to optimize drug usage. Variability in utilization rates across regions indicates the need for research on factors responsible. Precise understanding of dosing trends requires access to deidentified, individual dosing data.
Medicina (B Aires). 2007; 67(6 Pt 1): 543-55
Legido A, Valencia I, Katsetos CD, Delivoria-Papadopoulos M
The aim of this paper is to review the results of recent clinical studies of some therapies that have demonstrated a neuroprotective effect in perinatal hypoxic-ischemic encephalopathy (HIE) and to present the future perspectives of other clinical and basic research investigations. THERAPIES WITH DEMONSTRATED CLINICAL EFFICACY: ALLOPURINOL: It blocks the production of free radicals following hypoxia-ischemia. In a recent study, infants with hypoplastic left heart syndrome treated with allopurinol, but not those with other congenital cardiopathies, had significantly less number of complications than controls, including death, seizures, coma or cardiac events. OPIOIDS: In another recent study, newborns with HIE treated with morphine or phentanyl, had less severe brain damage on MRI and a better neurological outcome. HYPOTHERMIA: Both local (head cooling) or systemic (whole body) hypothermia have a neuroprotective effect in selected newborns with HIE. FUTURE PERSPECTIVES: ANTIEPILEPTIC DRUGS: They have multiple mechanisms of action that can block the biochemical cascade of neuronal damage in HIE. OTHER THERAPEUTIC MODALITIES: Among them the following should be emphasized: combined neuroprotective treatments, growth factors, genetic therapies, stem cell transplant, and neuroprotective immunization. In conclusion, a better knowledge of the molecular mechanisms of HIE pathogenesis and better clinical studies of neuroprotective therapies will open new possibilities aplicable to clinical practice. These advances will undoubtedly improve the prognosis of newborns with HIE.